The role of leptin in reproductive function

• Applicant: Dr. Maximilian Michel
• Subject Area: Animal Physiology and Biochemistry
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466254524

The key genes involved in energy homeostasis are conserved across vertebrates from mammals to fish. Leptin in mammals is primarily expressed in adipose tissue in direct proportion to body fat and signals the status of peripheral energy stores to the brain. However, the role of leptin in non-mammalian vertebrates is unclear. Leptin is not expressed in fish adipose tissue and knockout of hormone or receptor do not lead to an obese phenotype as opposed to mammals. Our preliminary data suggest that leptin plays a role in energy flux in and out of gonadal tissue in female zebrafish. This poses two intriguing venues for research: 1) From a human, comparative biological perspective - the zebrafish allows us to study the role of leptin in the absence of morbid obesity. In mammals, leptin is involved with subfertility in obesity, but the mechanisms are unclear. Characterization of peripheral leptin effects in zebrafish reproductive biology will shed light on ancestral mechanisms gone awry in obese patients with high circulating leptin levels. 2) Leptin appears to play a role in both the growth as well as the (re)absorption / breakdown of oocytes. Oocytes in gravid fish make up a significant proportion of body weight and recovery of energy from oocytes has been hypothesized. From an evolutionary biology perspective: are oocytes an ancestral energy storage organ and what is the partial role of leptin in this?In summary, I propose that leptin levels in fish rise during fasting leading to a recruitment of energy from mature oocytes. These compose up to 25% of total body mass, 80% of which being energy containing egg yolk in gravid fish. While tapping this significant energy source, I propose that leptin drives maturation via aromatase -> estrogen -> vitellogenin in order to retain a basal level of reproductive competence during times of food deprivation. I propose the following independent aims. 1) How does leptin interact with the peripheral steroid systems in order to modulate oocyte maturation? 2) Fasting leads to the resorption of oocytes. Is this oocyte derived energy used by the fasting female and what is the role of leptin in this process? 3) The fish leptin gene is duplicated. We will characterize gene expression and loss of function separately and produce recombinant protein sources, antibodies and tissue specific loss of function lines that will be critical to further dissect the role of leptin in a follow up application. We will expose immature and mature oocytes to the recombinant zebrafish leptin and perform RNAseq in order to test whether different paralogs of leptin and/or the stage of oocytes mitigate the role of leptin in maturation (aim1) versus resorption (aim2). This will identify key nodes for further investigation.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professorin Berta Levavi-Sivan, Ph.D.